Application of compound or traditional chinese medicine extract in preparation of nucleic acid delivery agent and related products thereof

Abstract

The present application relates to extracting a plurality of compounds from a traditional Chinese medicine, or synthesizing a compound capable of promoting nucleic acid delivery, and utilizing the extracted compound, or a plurality of combinations to promote absorption and entry of a nucleic acid such as sRNA into a target cell, and to facilitate the entry of a nucleic acid into a target site in a subject in need thereof.

1 - 66 . (canceled) 
     
     
         67 . A method of delivering a nucleic acid using a lipid composition, comprising
 mixing the lipid composition with the nucleic acid to obtain a lipid nucleic acid mixture, and   delivering the lipid nucleic acid mixture so that the nucleic acid is delivered,   wherein the lipid composition comprising one or more compounds having the following formula:   
       
         
           
           
               
               
           
         
         wherein L 1 , L 2 , and L 3  are each independently selected from the group consisting of null, —C(O)O—CH 2 —, —CH(OH)—, —C(O)—NH—CH 2 —, —CH 2 —OC(O)—, —CH 2 —NH—C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NH—C(O)—, —CH 2 —, 
       
       
         
           
           
               
               
           
         
         with the proviso that at most two of L 1 , L 2  and L 3  are null; 
         with respect to the divalent groups L 1  and L 2 , the dash “-” on the left side is linked to the groups A and B, respectively, and the dash “-” on the right side is linked to the central carbon atom; 
         with respect to the divalent group L 3 , the dash “-” on the left side is linked to the central carbon atom, and the dash “-” on the right side is linked to the group Q; 
         A, B and Q are each independently selected from the group consisting of H, —OH, C 1-20  alkyl, C 1-20  alkenyl, C 1-20  heteroalkyl, C 1-20  heteroalkenyl, —NH 2 , and —NR 3   + , R is each independently H or C 1-6  alkyl; and 
         n is an integer 0, 1, 2, 3 or 4; 
       
     
     
         68 . The method of  claim 67 , wherein the nucleic acid is delivered by oral administration, inhalation or injection. 
     
     
         69 . The method of  claim 67 , wherein the nucleic acid is delivered to a target cell. 
     
     
         70 . The method of  claim 67 , wherein the nucleic acid is delivered to a subject in need thereof. 
     
     
         71 . The method of  claim 70 , wherein the nucleic acid treats a disease in the subject. 
     
     
         72 . The method of the  claim 71 , wherein the disease is a cancer. 
     
     
         73 . The method of  claim 67 , wherein lipid nucleic acid is obtained by a boiling method, a reverse evaporation method, or by direct mixing. 
     
     
         74 . The method of  claim 73 , wherein the temperature of the boiling method being selected from group consisting of a range of 25° C. to 100° C., a range of 50° C. to 100° C., a range of 80° C. to 100° C., and a range of 95° C. to 100° C. 
     
     
         75 . The method of  claim 73 , wherein the boiling method comprises adding an organic solvent solution of the lipid composition to an aqueous solution of the nucleic acid. 
     
     
         76 . The method of  claim 73 , wherein the temperature of the reverse evaporation method is 25° C. to 70° C., 30° C. to 65° C., or 40° C. to 60° C. 
     
     
         77 . The method of  claim 73 , wherein the reverse evaporation method comprises adding an aqueous solution of the nucleic acid to an organic solvent solution of the lipid composition. 
     
     
         78 . The method of  claim 67 , wherein
 L 1  is selected from the group consisting of null, —C(O)O—CH 2 — and —CH(OH)—,   L 2  is selected from the group consisting of null, —C(O)O— and —C(O)NH—,   L 3  is selected from the group consisting of null, —C(O)O—, —CH 2 —OC(O)—, —CH 2 — and   
       
         
           
           
               
               
           
         
         A is selected from the group consisting of H, —OH, C 1-20  alkyl and C 1-20  alkenyl; 
         B is selected from the group consisting of H, —OH, —NH 2 , C 1-20  alkyl and C 1-20  alkenyl; 
         Q is selected from the group consisting of H, —OH, C 1-20  alkyl and C 1-20  alkenyl, —NH 2 , and —NR 3   + , wherein R is H or C 1-6  alkyl. 
       
     
     
         79 . The method of  claim 78 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 A is selected from the group consisting of a linear C 15-18  alkyl group and a linear C 15-18  alkenyl group; 
 B is selected from the group consisting of a linear C 15-18  alkyl group and a linear C 15-18  alkenyl group; 
 Q is selected from the group consisting of H, —OH, a linear C 15-18  alkyl group and a linear C 15-18  alkenyl group, and —NR 3   + , wherein R is H or methyl; and 
 L 3  is —C(O)O—. 
 
     
     
         80 . The method of  claim 67 , wherein the lipid composition comprises any one or more lipids selected from Table 1, or a combination of the any one or more lipids selected from Table 1 with any one or more other lipids and other related chemicals. 
     
     
         81 . The method of  claim 80 , wherein the lipid composition comprises any one or more lipids selected from the following group, or a combination thereof with any one or more other lipids and other related chemicals: 
       
         
           
           
               
               
           
         
       
     
     
         82 . The method of  claim 67 , wherein the nucleic acid is a small nucleic acid. 
     
     
         83 . The method of  claim 67 , wherein the nucleic acid is single stranded or double stranded. 
     
     
         84 . The method of  claim 67 , wherein the nucleic acid has a stem-loop structure. 
     
     
         85 . The method of  claim 67 , wherein the nucleic acid has a length of 14-32 bp, 16-28 bp or 18-24 bp. 
     
     
         86 . A compound having the following structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         87 . A pharmaceutical composition, comprising a lipid composition and a nucleic acid, wherein the lipid composition comprises one or more compounds having the following formula: 
       
         
           
           
               
               
           
         
         wherein L 1 , L 2 , and L 3  are each independently selected from the group consisting of null, —C(O)O—CH 2 —, —CH(OH)—, —C(O)—NH—CH 2 —, —CH 2 —OC(O)—, —CH 2 —NH—C(O)—, —C(O)O—, —C(O)NH—, —OC(O)—, —NH—C(O)—, —CH 2 —, 
       
       
         
           
           
               
               
           
         
         with the proviso that at most two of L 1 , L 2  and L 3  are null; 
         A, B and Q are each independently selected from the group consisting of H, —OH, C 1-20  alkyl, C 1-20  alkenyl, C 1-20  heteroalkyl, C 1-20  heteroalkenyl, —NH 2 , and —NR 3   + , R is H or C 1-6  alkyl; and 
         n is an integer 0, 1, 2, 3 or 4. 
       
     
     
         88 . The pharmaceutical composition of  claim 87 , wherein the pharmaceutical composition is formulated so that it can be administered via oral administration, inhalation, digestive tract or respiratory tract. 
     
     
         89 . The pharmaceutical composition of  claim 87 , wherein at least part of or all of the lipid composition and the nucleic acid exist in the form of a mixture. 
     
     
         90 . The pharmaceutical composition of  claim 87 , wherein the pharmaceutical composition is provided in the form of a kit, the lipid composition and the nucleic acid in the kit being each independently provided in a first container and a second container, the first container and the second container being the same or different. 
     
     
         91 . A method for the manufacture of a pharmaceutical composition, comprising adding an organic solvent solution comprising a lipid to an aqueous solution of a nucleic acid, and subsequently heating at a temperature selected from the group consisting of a range of 25° C. to 100° C., a range of 50° C. to 100° C., a range of 80° C. to 100° C., and a range of 95° C. to 100° C. to obtain the pharmaceutical composition. 
     
     
         92 . A lipid composition selected from any one of the following: a lipid combination of No. 8:No. 41=6:1; a lipid combination of No. 38:No. 41=6:1; a lipid combination of No. 39:No. 41=6:1; a lipid combination of No. 40:No. 41=6:1; a lipid combination of No. 38:No. 12:No. 41:No. 29=1:1:2:1; a lipid combination of No. 40:No. 12:No. 41=2:4:3; a lipid combination of No. 12:No. 41=1:6; a lipid combination of No. 12:No. 41=1:1; a lipid combination of No. 12:No. 41=6:1; a lipid combination of No. 40:No. 12:No. 41=2:2:2; a lipid combination of No. 4:No. 12:No. 41=1:1:1; DG combination of No. 1:No. 2:No. 3:No. 19:No. 35=1:1:1:1:1; TG combination of No. 6:No. 9:No. 10:No. 13:No. 15:No. 16:No. 18:No. 20:No. 21:No. 22:No. 23:No. 24:No. 25:No. 26:No. 27:No. 28:No. 32:No. 33=1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1; LPC combination of No. 36:No. 37=1:1; PC combination of No. 11:No. 12=1:1; PE combination of No. 8:No. 38=1:1; Cer combination of No. 4:No. 14=1:1; So combination of No. 17:No. 30:No. 31=1:1:1; an equal volume combination of No. 1-36 without No. 5, No. 7; an equal volume combination of No. 1-36 without No. 5, No. 7, No. 34; an equal volume combination of No. 1-36 without No. 5, No. 7, No. 1, No. 2, No. 3, No. 19, No. 35; an equal volume combination of No. 1-36 No. 5, No. 7, No. 6, No. 9, No. 10, No. 13, No. 15, No. 16, No. 18, No. 20, No. 21, No. 22, No. 23, No. 24, No. 25, No. 26, No. 27, No. 28, No. 32, No. 33; an equal volume combination of No. 1-36 without No. 5, No. 7, No. 36, No. 37; an equal volume combination of No. 1-36 without No. 5, No. 7, No. 11, No. 12; an equal volume combination of No. 1-36 without No. 5, No. 7, No. 8 in; an equal volume combination of No. 1-36 without No. 5, No. 7, No. 4, No. 14; an equal volume combination of No. 1-36 without No. 5, No. 7, No. 29; a lipid combination of No. 1:No. 34=2:1; a lipid combination of No. 1: the DG composition=2:1; a lipid combination of No. 1: the TG composition=2:1; a lipid combination of No. 1: the LPC composition=2:1; a lipid combination of No. 1:No. 8=2:1; a lipid combination of No. 1:No. 12=2:1; a lipid combination of No. 1: the Cer composition=2:1; a lipid combination of No. 1: the So composition=2:1; a lipid combination of No. 1:No. 29=2:1; a lipid combination of No. 1:No. 8:No. 12=1:1:1; a lipid combination of No. 8:No. 34=2:1; a lipid combination of No. 8: the DG composition=2:1; a lipid combination of No. 8: the TG composition=2:1; a lipid combination of No. 8: the LPC composition=2:1; a lipid combination of No. 8:No. 37=4:1; a lipid combination of No. 8:No. 12=2:1; a lipid combination of No. 8: the Cer composition=2:1; a lipid combination of No. 8: the So composition=2:1; a lipid combination of No. 8:No. 31=6:1; a lipid combination of No. 8:No. 29=2:1; a lipid combination of No. 12:No. 34=2:1; a lipid combination of No. 12: the DG composition=2:1; a lipid combination of No. 12: the TG composition=2:1; a lipid combination of No. 12: the LPC composition=2:1; a lipid combination of No. 12:No. 8=2:1; a lipid combination of No. 12: the Cer composition=2:1; a lipid combination of No. 12: the So composition=2:1; a lipid combination of No. 12:No. 29=2:1; a lipid combination of No. 12:No. 8:No. 1&2=2:1:1; a lipid combination of No. 12:No. 8:No. 15=2:1:1; a lipid combination of No. 12:No. 8:No. 36&37=2:1:1; a lipid combination of No. 12:No. 8:No. 11=2:1:1; a lipid combination of No. 12:No. 8:No. 12=2:1:1; a lipid combination of No. 12:No. 8:No. 4=2:1:1; a lipid combination of No. 12:No. 8:No. 31=2:1:1; a lipid combination of No. 12:No. 8:No. 29=2:1:1; a lipid combination of No. 12:No. 8:No. 34=3:2:1; a lipid combination of No. 12:No. 8:No. 34=4:2:3; a lipid combination of No. 12:No. 8:No. 2=4:2:3; a lipid combination of No. 12:No. 8:No. 2=16:8:3; a lipid combination of No. 12:No. 8:No. 32=4:2:3; a lipid combination of No. 12:No. 8:No. 37=4:2:3; a lipid combination of No. 12:No. 8:No. 11=4:2:3; a lipid combination of No. 12:No. 8:No. 38=4:2:3; a lipid combination of No. 12:No. 8:No. 4=4:2:3; a lipid combination of No. 12:No. 8:No. 31=4:2:3; a lipid combination of No. 12:No. 8:No. 29=4:2:3; a lipid combination of No. 12:No. 8:No. 29:No. 31=2:1:1:1; a lipid combination of No. 12:No. 8:No. 29:No. 31:No. 34=4:2:2:2:5; a lipid combination of No. 12:No. 8:No. 29:No. 31:No. 2=4:2:2:2:5; a lipid combination of No. 12:No. 8:No. 29:No. 31:No. 32=4:2:2:2:5; a lipid combination of No. 12:No. 8:No. 29:No. 31:No. 11=4:2:2:2:5; a lipid combination of No. 12:No. 8:No. 29:No. 31:No. 37=4:2:2:2:5; a lipid combination of No. 12:No. 8:No. 29:No. 31:No. 38=4:2:2:2:5; a lipid combination of No. 12:No. 8:No. 29:No. 31:No. 4=4:2:2:2:5; a lipid combination of No. 12:No. 8:No. 29:No. 31:No. 4:No. 1:No. 16=2:1:1:3:2:2:3; a lipid combination of No. 1:No. 8:No. 12:No. 1&2=2:2:2:3; a lipid combination of No. 1:No. 8:No. 12:No. 15=2:2:2:3; a lipid combination of No. 1:No. 8:No. 12:No. 36&37=2:2:2:3; a lipid combination of No. 1:No. 8:No. 12:No. 12=2:2:2:3; a lipid combination of No. 1:No. 8:No. 12:No. 4=2:2:2:3; a lipid combination of No. 1:No. 8:No. 12:No. 31=2:2:2:3; a lipid combination of No. 1:No. 8:No. 12:No. 29=2:2:2:3; a lipid combination of No. 8:No. 34:No. 1&2=2:1:1; a lipid combination of No. 8:No. 34:No. 15=2:1:1; a lipid combination of No. 8:No. 34:No. 36&37=2:1:1; a lipid combination of No. 8:No. 34:No. 12=2:1:1; a lipid combination of No. 8:No. 34:No. 4=2:1:1; a lipid combination of No. 8:No. 34:No. 31=2:1:1; a lipid combination of No. 8:No. 34:No. 29=2:1:1; a lipid combination of No. 8:No. 31:No. 34=12:3:5; a lipid combination of No. 8:No. 31:No. 2=12:3:5; a lipid combination of No. 8:No. 31:No. 37=12:3:5; a lipid combination of No. 8:No. 31:No. 11=12:3:5; a lipid combination of No. 8:No. 31:No. 12=12:3:5; a lipid combination of No. 8:No. 31:No. 4=12:3:5; a lipid combination of No. 8:No. 31:No. 29=12:3:5; a lipid combination of No. 8:No. 31:No. 32=12:3:5; a lipid combination of No. 8:No. 4:No. 34=12:3:5; a lipid combination of No. 8:No. 4:No. 2=12:3:5; a lipid combination of No 0.8:No. 4:No. 37=12:3:5; a lipid combination of No. 8:No. 4:No. 12=12:3:5; a lipid combination of No. 8:No. 4:No. 31=12:3:5; a lipid combination of No. 8:No. 4:No. 29=12:3:5; a lipid combination of No. 8:No. 4:No. 32=12:3:5; a lipid combination of No. 38:No. 34=2:1; a lipid combination of No. 38:No. 1=2:1; a lipid combination of No. 38:No. 2=2:1; a lipid combination of No. 38:No. 1&2=2:1; a lipid combination of No. 38:No. 15=2:1; a lipid combination of No. 38:No. 32=2:1; a lipid combination of No. 38:No. 37=2:1; a lipid combination of No. 38:No. 37=4:1; a lipid combination of No. 38:No. 11=2:1; a lipid combination of No. 38:No. 12=2:1; a lipid combination of No. 38:No. 11&12=2:1; a lipid combination of No. 38:No. 12=4:1; a lipid combination of No. 38:No. 8=2:1; a lipid combination of No. 38:No. 4=2:1; a lipid combination of No. 38:No. 30=2:1; a lipid combination of No. 38:No. 31=2:1; a lipid combination of No. 38:No. 29=2:1; a lipid combination of No. 1:No. 38:No. 12:No. 34=2:2:2:3; a lipid combination of No. 1:No. 38:No. 12:No. 15=2:2:2:3; a lipid combination of No. 1:No. 38:No. 12:No. 37=2:2:2:3; a lipid combination of No. 1:No. 38:No. 12:No. 8=2:2:2:3; a lipid combination of No. 1:No. 38:No. 12:No. 4=2:2:2:3; a lipid combination of No. 1:No. 38:No. 12:No. 31=2:2:2:3; a lipid combination of No. 1:No. 38:No. 12:No. 29=2:2:2:3; a lipid combination of No. 38:No. 34:No. 1=2:1:3; a lipid combination of No. 38:No. 34:No. 15=2:1:3; a lipid combination of No. 38:No. 34:No. 37=2:1:3; a lipid combination of No. 38:No. 34:No. 12=2:1:3; a lipid combination of No. 38:No. 34:No. 8=2:1:3; a lipid combination of No. 38:No. 34:No. 4=2:1:3; a lipid combination of No. 38:No. 34:No. 31=2:1:3; a lipid combination of No. 38:No. 34:No. 29=2:1:3; a lipid combination of No. 38:No. 12:No. 1=2:1:3; a lipid combination of No. 38:No. 12:No. 2=4:1:3; a lipid combination of No. 38:No. 12:No. 15=2:1:3; a lipid combination of No. 38:No. 12:No. 37=2:1:3; a lipid combination of No. 38:No. 12:No. 8=2:1:3; a lipid combination of No. 38:No. 12:No. 4=2:1:3; a lipid combination of No. 38:No. 12:No. 31=2:1:3; a lipid combination of No. 38:No. 12:No. 29=2:1:3; a lipid combination of No. 38:No. 12:No. 1:No. 15:No. 34=22:22:22:33:36; a lipid combination of No. 38:No. 12:No. 1:No. 15:No. 37=22:22:22:33:36; a lipid combination of No. 38:No. 12:No. 1:No. 15:No. 4=22:22:22:33:36; a lipid combination of No. 38:No. 12:No. 1:No. 15:No. 31=22:22:22:33:36; a lipid combination of No. 38:No. 12:No. 1:No. 15:No. 29=22:22:22:33:36; a lipid combination of No. 38:No. 34:No. 37:No. 1=44:22:33:36; a lipid combination of No. 38:No. 34:No. 37:No. 15=44:22:33:36; a lipid combination of No. 38:No. 34:No. 37:No. 12=44:22:33:36; a lipid combination of No. 38:No. 34:No. 37:No. 4=44:22:33:36; a lipid combination of No. 38:No. 34:No. 37:No. 31=44:22:33:36; a lipid combination of No. 38:No. 12:No. 4:No. 34=44:22:33:36; a lipid combination of No. 38:No. 12:No. 4:No. 1=44:22:33:36; a lipid combination of No. 38:No. 12:No. 4:No. 15=44:22:33:36; a lipid combination of No. 38:No. 12:No. 4:No. 37=44:22:33:36; a lipid combination of No. 38:No. 12:No. 4:No. 37=8:2:5:3; a lipid combination of No. 38:No. 12:No. 4:No. 31=44:22:33:36; a lipid combination of No. 38:No. 12:No. 4:No. 29=44:22:33:36; a lipid combination of No. 38:No. 12:No. 4:No. 29:No. 34=88:44:66:72:135; a lipid combination of No. 38:No. 12:No. 4:No. 29:No. 1=88:44:66:72:135; a lipid combination of No. 38:No. 12:No. 4:No. 29:No. 15=88:44:66:72:135; a lipid combination of No. 38:No. 12:No. 4:No. 29:No. 37=88:44:66:72:135; a lipid combination of No. 38:No. 12:No. 4:No. 29:No. 31=88:44:66:72:135; a lipid combination of No. 38:No. 12:No. 4:No. 2=20:10:15:9; a lipid combination of No. 38:No. 12:No. 4:No. 6=20:10:15:9; a lipid combination of No. 38:No. 12:No. 4:No. 17=20:10:15:9; a lipid combination of No. 38:No. 12:No. 4:No. 29=20:10:15:9; a lipid combination of No. 38:No. 12:No. 4:No. 34=20:10:15:9; a lipid combination of No. 38:No. 12:No. 4:No. 37=20:10:15:9; a lipid combination of No. 38:No. 12:No. 31:No. 34=2:1:3:3; a lipid combination of No. 38:No. 12:No. 31:No. 1=2:1:3:3; a lipid combination of No. 38:No. 12:No. 31:No. 15=2:1:3:3; a lipid combination of No. 38:No. 12:No. 31:No. 37=2:1:3:3; a lipid combination of No. 38:No. 12:No. 31:No. 4=2:1:3:3; a lipid combination of No. 38:No. 12:No. 31:No. 29=2:1:3:3; a lipid combination of No. 38:No. 34:No. 37:No. 31:No. 1=88:44:66:72:135; a lipid combination of No. 38:No. 34:No. 37:No. 31:No. 15=88:44:66:72:135; a lipid combination of No. 38:No. 34:No. 37:No. 31:No. 12=88:44:66:72:135; a lipid combination of No. 38:No. 34:No. 37:No. 31:No. 4=88:44:66:72:135; a lipid combination of No. 38:No. 34:No. 37:No. 31:No. 29=88:44:66:72:135; a lipid combination of No. 38:No. 37:No. 34=4:2:3; a lipid combination of No. 38:No. 37:No. 1=4:2:3; a lipid combination of No. 38:No. 37:No. 2=4:2:3; a lipid combination of No. 38:No. 37:No. 1&2=4:2:3; a lipid combination of No. 38:No. 37:No. 2=32:8:5; a lipid combination of No. 38:No. 37:No. 32=32:8:5; a lipid combination of No. 38:No. 37:No. 15=4:2:3; a lipid combination of No. 38:No. 37:No. 32=4:2:3; a lipid combination of No. 38:No. 37:No. 8=4:2:3; a lipid combination of No. 38:No. 37:No. 11=4:2:3; a lipid combination of No. 38:No. 37:No. 12=4:2:3; a lipid combination of No. 38:No. 37:No. 11&12=4:2:3; a lipid combination of No. 38:No. 37:No. 12=4:1:1; a lipid combination of No. 38:No. 37:No. 4=4:2:3; a lipid combination of No. 38:No. 37:No. 30=4:2:3; a lipid combination of No. 38:No. 37:No. 31=4:2:3; a lipid combination of No. 38:No. 37:No. 29=4:2:3; a lipid combination of No. 8:No. 37:No. 32=4:1:2; a lipid combination of No. 8:No. 37:No. 2=4:1:2; a lipid combination of No. 38:No. 37:No. 15:No. 34=64:16:10:45; a lipid combination of No. 38:No. 37:No. 15:No. 1=64:16:10:45; a lipid combination of No. 38:No. 37:No. 15:No. 12=64:16:10:45; a lipid combination of No. 38:No. 37:No. 15:No. 4=64:16:10:45; a lipid combination of No. 38:No. 37:No. 15:No. 31=64:16:10:45; a lipid combination of No. 38:No. 37:No. 15:No. 29=64:16:10:45; a lipid combination of No. 38:No. 2:No. 37=4:2:3; a lipid combination of No. 38:No. 2:No. 31=4:2:3; a lipid combination of No. 38:No. 2:No. 29=4:2:3; a lipid combination of No. 38:No. 2:No. 34=4:2:3; a lipid combination of No. 38:No. 2:No. 32=4:2:3; a lipid combination of No. 38:No. 2:No. 12=4:2:3; a lipid combination of No. 38:No. 2:No. 12=4:5:1; a lipid combination of No. 38:No. 2:No. 4=4:2:3; No. 1&2, No. 11&12 and No. 36&37 represent lipids No. 1 and No. 2 in any ratio, lipids No. 11 and No. 12 in any ratio, lipids No. 36 and No. 37 in any ratio, respectively.